This invention relates to the controlled formation of particulate products using supercritical fluids. It provides a method and apparatus for the formation of substances in particulate form, and also the particulate product of the method.
The invention relates generally to the formation of particles of a substance of interest, from a solution or suspension of that substance in an appropriate vehicle, using a supercritical fluid to extract the vehicle and hence cause precipitation of a particulate product.
More particularly, it concerns modifications to an existing technique for particle formation using supercritical fluids, described in WO-95/01221 and (in a modified form) in WO-96/00610. The technique is known as xe2x80x9cSEDSxe2x80x9d (Solution Enhanced Dispersion by Supercritical Fluids). Its essence is that a solution or suspension of a substance of interest, in an appropriate vehicle, is co-introduced into a particle formation vessel with a supercritical fluid, in such a way that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid, and substantially immediately on introduction of the fluids into the vessel. The pressure and temperature inside the particle formation vessel are carefully controlled during this process.
SEDS allows a high degree of control over conditions such as pressure, temperature and fluid flow rates, and over the physical dispersion of the solution/suspension, at the exact point where particle formation occurs (ie, at the point where the vehicle is extracted into the supercritical fluid). It therefore allows excellent control over the size, shape and other physical and/or chemical properties of the particles formed.
The present invention builds on this existing technology. It provides a modification to the SEDS technique, which can lead to greatly improved control over the characteristics of the particulate product.
Accordingly, most of the technical features of SEDS, as disclosed in WO-95/01221 and WO-96/00610, apply also to the present invention. The technical information contained in the earlier publications, as to the execution of SEDS, is also applicable when carrying out the present invention and as such, WO-95/01221 and WO-96/00610 are intended to be read together with the present application.
According to a first aspect of the present invention there is provided a method for forming particles of a substance, the method comprising (a) introducing into a particle formation chamber, the temperature and pressure in which are controlled, a first supercritical fluid and a solution or suspension of the substance in a vehicle; (b) simultaneously introducing, into the particle formation chamber, an impinging flow of a second supercritical fluid, at an angle to, and directed at, the direction of flow of the first supercritical fluid; and (c) using either or both of the first and second supercritical fluids to disperse the solution or suspension, and to extract the vehicle from it, substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation chamber.
This method retains all the advantages of the SEDS technique. The simultaneous introduction of the solution or suspension and the supercritical fluids, into a chamber inside which pressure and temperature are controlled, allows a high degree of control of operating parameters at the exact point when the fluids come into contact with one another and therefore at the point of actual particle formation. Importantly, the mechanical action of the supercritical fluids is used to disperse the solution/suspension, whilst at the same time they extract the vehicle from itxe2x80x94because of this, controlling the relative flow rates of the fluids allows accurate control over the size of the fluid elements (eg, droplets) formed on dispersion of the solution/suspension, and hence of the particles formed substantially simultaneously by extraction of the vehicle into the supercritical fluid(s).
However, the method of the present invention allows for greatly improved dispersion of the solution or suspension of the substance of interest, by the additional impinging (preferably counter-current) flow of the second supercritical fluid. This improved dispersion can be attributed to enhanced physical contact between the solution/suspension and the (usually relatively high velocity and therefore also high kinetic energy) supercritical fluids, hence effecting the formation of very fine particles with an extremely narrow size distribution. The two supercritical fluid flows, directed at one another and usually in substantially opposite directions, each transfer their kinetic energy to the solution or suspension, serving to break it up into individual fluid elements; the size and size distribution of these elements can be very closely controlled by adjusting the flow rates of the various fluids and other working conditions such as the temperature and pressure inside the particle formation chamber. The solution/suspension can be subjected to a very high degree of dispersion due to the high overall supercritical fluid velocity (ie, high overall kinetic energy), and its efficient dispersion, at substantially the same time as the vehicle is extracted from it, in turn can provide a high degree of uniformity in the particles formed.
A further advantage of using two supercritical fluid flows, and hence introducing a higher level of kinetic energy into the solution/suspension at or near the point of particle formation, is that particles formed from the solution or suspension can be forced rapidly away from the point of particle formation and hence apparatus blockages (which might otherwise occur in the inlet means used to introduce the fluids into the particle formation chamber) can be reduced or even avoided. The supercritical fluids thus serve to disperse the solution or suspension, to extract the vehicle from it and to remove particulate products from the region of particle formation. The high velocities of the supercritical fluids facilitate quick removal of the particles, ensuring that they cannot reunite with fluid elements, aggregate with one another or otherwise clog up the region of particle formation.
The directions of flow of the first supercritical fluid and the solution or suspension may be substantially parallel, for instance coaxial, as described in WO-95/01221 and WO-96/00610. However, the solution or suspension may in the present invention be introduced at an angle (eg, of up to 90xc2x0) to the flow of the first supercritical fluid, so long as it is then dispersed by the supercritical fluid(s) immediately it comes into contact with them. Generally speaking, the directions of flow of all the fluids should be chosen so as to maximise the amount of physical contact between them in the region of particle formation; this in turn serves to maximise the amount of kinetic energy transferred from the supercritical fluids to the solution/suspension and to the particulate products, thus improving dispersion and more efficiently removing particles from areas of potential blockage. The use of two supercritical fluid flows together improves these processes yet further and ensures better control over the mechanism of particle formation.
According to a second aspect, the present invention provides apparatus suitable for carrying out the above described method. The apparatus comprises a particle formation chamber; means for controlling the temperature in the chamber at a desired level; means for controlling the pressure in the chamber at a desired level; first fluid inlet means for the introduction into the chamber of a first supercritical fluid and a solution or suspension of the substance of interest in a vehicle; and second fluid inlet means for introducing simultaneously an impinging flow of a second supercritical fluid, at an angle to, and directed at, the direction of flow of the first supercritical fluid, the apparatus being such as to allow dispersion of the solution or suspension, and extraction of the vehicle, to occur substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation chamber, by the action of either or both of the two supercritical fluids.
Again, the first fluid inlet means preferably allows the co-introduction of the first supercritical fluid and the solution or suspension, for instance in substantially parallel directions or even coaxially.
In both first and second aspects of the invention, the second supercritical fluid preferably flows in a direction substantially opposite to that of the first, ie, the angle at which it is directed at the first supercritical fluid flow is preferably about 180xc2x0. However, other impinging angles may be chosen, again the general idea being to maximise physical contact between the fluids in the region of particle formation. The first and second supercritical fluids will usually, although not necessarily, meet at or very close to the point of particle formation, ie, the point at which they contact the solution or suspension.
In the present invention, and the current description of it, the term xe2x80x9csupercritical fluidxe2x80x9d means a fluid substantially at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range (1.01-7.0)Pc, and its temperature in the range (1.01-4.0)Tc.
The term xe2x80x9cvehiclexe2x80x9d means a fluid which is able to carry a solid or solids in solution or suspension. A vehicle may be composed of one or more component fluids. The vehicle used in the present invention should he substantially soluble in the chosen supercritical fluids, to allow its extraction at the point of particle formation.
The term xe2x80x9csupercritical solutionxe2x80x9d, as used herein, means one or more supercritical fluids together with one or more vehicles which it or they have extracted and dissolved. The solution will usually, although not necessarily, itself be in the supercritical state, at least within the particle formation chamber.
The verb xe2x80x9cdispersexe2x80x9d, unless the context clearly requires otherwise, refers to the formation of droplets, or of other analogous fluid elements, of the solution or suspension and/or of the vehicle.
The substance to which the method of the invention is applied may be any substance which needs to be produced in particulate form. It may be a substance for use in or as a pharmaceutical. However, the particulate product may also be a product of use in the ceramics, explosives or photographic industries; a foodstuff; a dye; a coating; etc. In each case, the principle behind the method of the invention remains the same; the technician need only adjust operating conditions in order to effect proper control over the characteristics of the particles being formed.
The substance may be in a single or multi-component formxe2x80x94it could for instance comprise an intimate mixture of two materials, or one material in a matrix of another, or one material coated onto a substrate of another, or other similar mixtures. The particulate product, formed from the substance using the method of the invention, may also be in a multi-component formxe2x80x94such products may be made from solutions or suspensions containing only single component starting materials, provided the solutions/suspensions are introduced with the supercritical fluids in the correct manner (more than one solution/suspension may be introduced into the particle formation chamber with the supercritical fluids). The particulate product may also be a substance formed from an in situ reaction (ie, immediately prior to, or on, dispersion by the supercritical fluid(s)) between two or more reactant substances, each carried by an appropriate vehicle. Such modifications to the SEDS process, involving the use of in situ reactions and/or more than one solution or suspension of a substance of interest, are described in WO-95/01221 and WO-96/00610, and can also be applied when carrying out the present invention.
Each of the first and second supercritical fluids may be any suitable supercritical fluid, for instance supercritical carbon dioxide, nitrogen, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, trifluoromethane or mixtures thereof. A particularly preferred supercritical fluid is supercritical carbon dioxide, due to its relatively low cost, toxicity, flammability and critical temperature.
The second and first supercritical fluids are preferably, but not necessarily, the same; again, conveniently both are supercritical carbon dioxide.
Either or both of the supercritical fluids may optionally contain one or more modifiers, for example methanol, ethanol, isopropanol, acetone or water. When used, a modifier preferably constitutes not more than 20%, and more preferably between 1% and 10%, mole fraction of the supercritical fluid. The term xe2x80x9cmodifierxe2x80x9d is itself well known to those skilled in the art. A modifier (or co-solvent) may be described as a chemical which, when added to a supercritical fluid, changes the intrinsic properties of the fluid in or around its critical point.
The vehicle may be any appropriate fluid which either dissolves or suspends the substance of interest and is itself substantially soluble in the chosen supercritical fluids. The choice of vehicle in any particular case will depend on the nature of the substance, on the supercritical fluids and on other practical criteria including those governing the desired end product. The term xe2x80x9cvehiclexe2x80x9d encompasses a mixture of two or more fluids which together have the necessary characteristics vis-a-vis the substance of interest and the supercritical fluids.
The choice of a suitable combination of supercritical fluids, modifier (where desired) and vehicle for any desired product will be well within the capabilities of a person of ordinary skill in the art.
The relative flow rates of the fluids introduced into the particle formation chamber may be used to control the size, size distribution and other characteristics of the particles formed. Each fluid flow rate may be separately adjusted. Preferably, the flow rates of the two supercritical fluids are much higher than that of the solution or suspension. Typically, the ratio of the solution/suspension flow rate to each supercritical fluid flow rate will be between 0.001 and 0.2, preferably between 0.001 and 0.1, more preferably between 0.01 and 0.07. However, the fluid flow rates chosen in any particular case will depend entirely on the substance of interest and the types of fluids being used.
The flow rates of the supercritical fluids, relative to that of the solution/suspension, are particularly important because the supercritical fluids act to disperse the solution/suspension and to remove particles from the region of particle formation. Their flow rates therefore affect the size of the fluid elements caused by the dispersion, and hence of the particles formed by extracting the vehicle from those fluid elements. They also help to avoid blockages in the particle formation apparatus.
Through the pressure and temperature control in the particle formation chamber (and control of the fluid flow rates), supercritical conditions may be maintained in the chamber at all times. The flow rates of the supercritical fluids relative to that of the solution or suspension, and the pressures and temperatures of the fluids, should be sufficient to allow the supercritical fluids to accommodate the vehicle (generally, the vehicle will represent no more than around 5% mole fraction of the supercritical fluids), so that the vehicle can be extracted from the solution/suspension to cause particle formation. Careful selection of such operating conditions can ensure the existence of only a single phase during most of the particle formation process, in the solution containing the supercritical fluids and the extracted vehicle. This in turn allows improved control over particle characteristics and substantially eliminates the risk of residual vehicle in the particulate product.
The fluids are preferably introduced into the particle formation chamber through fluid inlet means of the type described below in connection with the apparatus of the invention. Ideally, fluids should be made to flow in a smooth, continuous and preferably substantially pulse-less manner. This helps prevent draw-back of fluids into the inlet means, which could lead to particle precipitation in undesirable locations and blocking of apparatus.
The temperature in the particle formation chamber may be maintained at a desired level (preferably xc2x10.1xc2x0 C.) by means of a heating jacket or an oven. The pressure in the chamber is conveniently maintained at a desired level (preferably xc2x12 bar) by means of a back-pressure regulator.
The precise temperatures and pressures used will depend upon the choice of supercritical fluids and whether or not modifiers are present. These conditions, together with the flow rates of the fluids, and the concentration of the substance in the vehicle, are the main variables which may be adjusted to control parameters such as size, size distribution, shape and crystalline form in the particulate product.
The method of the invention preferably additionally involves collecting the particles following their formation, more preferably in the particle formation chamber itself. The method may also involve recovering the solution formed on extraction of the vehicle into the supercritical fluid(s), separating the components of the solution and recycling one or more of those components for future use. In particular, either or both of the supercritical fluids may be removed, purified and recycled.
The method is preferably carried out in a substantially continuous, as opposed to batch-wise, manner. This means that the formation and collection of particles, and/or the recovery and recycling of fluids, are preferably carried out continuously.
In apparatus according to the second aspect of the invention, the first and second fluid inlet means preferably comprise first and second nozzles respectively The first fluid inlet means may in fact comprise two nozzles, one for introduction of the first supercritical fluid and one for introduction of the solution or suspension, arranged at an appropriate angle relative to one another. The first and second fluid inlet means may both form part of a single fluid inlet assembly usable to introduce all fluids into the particle formation chamber in the appropriate manner.
A preferred fluid inlet assembly comprises two main components:
a) a first, xe2x80x9cprimaryxe2x80x9d nozzle having two or more concentric passages, through which may be introduced a flow of the first supercritical fluid and a flow of the solution or suspension of the substance of interest; and
b) a second, xe2x80x9csecondaryxe2x80x9d nozzle having at least one passage directed at an angle to the primary nozzle passages, through which secondary nozzle passage a flow of the second supercritical fluid may be introduced,
the outlets of the primary and secondary nozzle passages being positioned so as to allow supercritical fluid flowing through the secondary nozzle to impinge upon supercritical fluid flowing through the primary nozzle.
Preferably, the secondary nozzle passage is coaxial with the primary nozzle passages but points in the opposite direction, so that the outlet end of the secondary nozzle passage faces the outlet ends of the primary nozzle passages.
The primary nozzle passages may be of the type which allow xe2x80x9cpre-filmingxe2x80x9d or xe2x80x9csheathingxe2x80x9d of at least one of the fluids to occur, immediately prior to its contact with the other fluid(s). Typically, the primary nozzle may be used to cause pre-filming of the solution or suspension, immediately prior to its dispersion by the supercritical fluid(s). This means that the dimensions of the primary nozzle passages, and the relative positions of their outlets, must be such that a fluid entering through one passage is formed, as it reaches the outlet of that passage, into a thin film or sheath by its contact with, say, the lip of an adjacent passage outlet. This film or sheath can then be stretched (destabilised, and ultimately dispersed into separate fluid elements, when it comes into contact with a stream of a high velocity fluid in another nozzle passage and/or with an impinging stream from the secondary nozzle. Clearly, the thickness of the film or sheath, and hence the size of the fluid elements formed on dispersion, will depend on the relative flow rates of the fluids, and also on the nozzle geometry.
The outlets of the primary nozzle passages should be reasonably close to that of the secondary nozzle passage, again so as to maximise kinetic energy transfer between the second supercritical fluid and the solution/suspension. The actual distance and angle between them will depend, for instance, on the size, type and shape of particles it is desired to form, on the nature of the substance and the fluids, on the fluid flow rates to be used, on manufacturing constraints, etc.
For the at least two primary nozzle passages, the outlet of an inner passage may occur either upstream or downstream of that of one or more of the surrounding outer passage(s) or at virtually the same location. In the first case, contact between a solution/suspension passing through the inner passage and a first supercritical fluid passing through a surrounding passage occurs inside the primary nozzle and before the two together contact the second supercritical fluid. Accordingly, a degree of dispersion and extraction can occur before further dispersion by the second supercritical fluid. Such an inlet assembly may also for example be used in carrying out in situ reactions, for instance between one component carried in the vehicle and another in the first supercritical fluid, or between two components carried in two separate vehicles down two out of three primary nozzle passages, which reactions take place just within the primary nozzle, immediately prior to extraction of the vehicle or vehicles and particle formation. It could further be used, for instance, in the preparation of coated particles or particles in which one component is impregnated in a matrix of another.
(An alternative way of using this xe2x80x9cfirst casexe2x80x9d primary nozzle would be to introduce the first supercritical fluid through the inner passage and the solution/suspension through a surrounding passage. The solution/suspension would form a conical film surrounding the outlet of the inner passage, the surface of which film would be destabilised by the high velocity supercritical fluid emerging from the inner passage, leading ultimately to dispersion of the solution/suspension.)
In the second case scenario, both the first and the second supercritical fluids can together act to disperse a solution or suspension passing through the inner primary nozzle passage. This can increase the level of control over the particle characteristics and so is often one of the preferred arrangements. In this case, in situ reactions, coating, impregnation and other multi-component operations may still be carried out, by introducing further components through additional secondary nozzle passages. The secondary nozzle may itself, therefore, comprise two or more concentric passages, so that solutions or suspensions of substances of interest, as well as the second supercritical fluid, may be introduced at an angle to the first supercritical fluid flow. The same comments apply to the two or more secondary nozzle passages, as regards the positions of their outlets, and the desirability of the pre-filming approach, as to the primary nozzle passages.
The fluid inlet assembly typically comprises an intermediate chamber located between the primary and the secondary nozzle outlets, in which chamber the fluids may meet and interact. This chamber is preferably shaped to direct the fluids and/or particles formed from them, away from the point at which the fluids meet. Since particle formation typically occurs virtually at the nozzle outlets, the intermediate chamber itself forms part of the particle formation chamber. The intermediate chamber could, for instance, be directed at an angle (including perpendicular) to the primary and secondary nozzle passages, and in use may be downwardly directed so as to allow gravity to contribute (together with the relatively high overall velocity of the two supercritical fluid flows) to removal of particulate products from the nozzle outlet region. The size and shape of the intermediate chamber may be used in part to determine the characteristics of the particles formed, and again to contribute towards efficient particle removal and to minimise the risk of solution droplets uniting with the particles and causing agglomeration. To this end, the intermediate chamber should be so sized and shaped as to maximise fluid turbulence in or around the region of particle formation, which again enhances physical contact between the fluids and aids dispersion of the solution/suspension and removal of particulate products.
The nozzle passages may conveniently be made of stainless steel; other suitable materials include sapphire, high performance ceramics and high performance polymers. Other aspects of the design of the inlet assembly, for instance the diameters of the nozzle passages and their outlets, the positioning of the primary and secondary nozzles relative to one another, the number of passages in each nozzle and the uses to which they may be put, are as disclosed in WO-95/01221 and WO-96/00610 (although these documents refer to nozzles providing only one direction of flow, their teachings may apply equally to the primary or the secondary nozzle passages of use in the apparatus of the present invention).
When carrying out the method of the invention using such an inlet assembly, the fluid flow rates are preferably chosen so that the precipitated particles are caused to leave the inlet assembly virtually as soon as they are formed, so as to avoid blocking of the nozzle passage outlets. Again, the design of the intermediate chamber may be chosen so as to help in this, by creating the desired flow characteristics in the region of particle formation.
According to a third aspect, the present invention provides a fluid inlet assembly of the type described above.
The invention also provides, according to a fourth aspect, a particulate product formed using the method of the first aspect and/or the apparatus of the second.